As of 2013, 36 nucleoside or nucleotide analogs approved by the FDA were available for medicinal use; of these, 11 are anticancer agents and 25 are antiviral drugs (Jordheim, L. P. et al., “Advances in the Development of Nucleoside and Nucleotide Analogues for Cancer and Viral Diseases,” Nature Reviews: Drug Discovery, 2013, 12, 447-464). The therapeutic utility of these analogs stems from their ability to interfere with the replication and function of cellular or viral nucleic acids. Their mechanisms of action involve inhibition of enzymes required for the synthesis and replication of cellular or viral nucleic acids, and/or their ability to be incorporated into nucleic acids.
Cancer and viruses are characterized by their ability to develop resistance to the drugs used against them in conventional therapies. This is particularly prevalent with analogs of nucleic acid components, such as nucleobase, nucleoside and nucleotide analogs, which act as antimetabolites. The practice of using a combination of different drugs was evolved to fight drug resistance, however, even combination chemotherapy could not eliminate the drug resistance problem, since cross resistance may also develop against multiple drugs. The increasing prevalence of these drug resistant cancers and viruses necessitates the continued discovery and development of new, more effective therapeutic agents.
5-Fluorouracil (FU), the prototype of the anticancer fluoropyrimidines, is an antimetabolite discovered in 1957 that is still in use alone or in combination with other anticancer agents, or with biological response modifiers, particularly in the treatment of colorectal and breast cancer. Major shortcomings of FU include inadequate oral bioavailabilty, severe toxic side effects, and pharmacogenetic liability in patients with a deficiency of FU degrading enzymes, which can be lethal. Over the past six decades, numerous prodrug derivatives of FU, as well as several nucleoside analogs and drug combinations have been developed to overcome toxic side effects, increase the therapeutic effectiveness and the therapeutic index. However, what remains is an unmet need of developing new, orally available anticancer fluoropyrimidines that are devoid of the maj or side effects, such as gastro-intestinal and bone marrow toxicity, hand and foot syndrome and pharmacogenetic syndrome (dihydropyrimidine dehydrogenase deficiency (DPD deficiency)), among others.
The fluoropyrimidine capecitabine (Xeloda®) is the sole nucleoside carbamate approved by the FDA and the most advanced fluoropyrimidine so far developed. It is a prodrug of 5-fluorouracil (FU). While sharing some of the shortcomings of FU, capecitabine is available orally, causes less GI toxicity characteristic of fluoropyrimidines by becoming activated primarily in the liver, and not during intestinal absorption. These advances have been attributed to the carbamate side chain at the N4-position of the 5-fluorocytosine moiety of this nucleoside analog. However, hand and foot syndrome is often the dose limiting toxicity of capecitabine leading to significant morbidity. Thymidine phosphorylase, the enzyme responsible for the obligatory conversion of capecitabine to the cytotoxic FU, has significant activity in some normal tissues, such as the palm, and may play a role in the etiology of hand and foot syndrome. Furthermore, inherited DPD deficiency, which can put patients at risk of severe or lethal toxicities, is also linked to FU that is an obligatory intermediate in the metabolic activation of capecitabine by thymidine phosphorylase.
There exists an ongoing and unmet need for nucleosides with less harmful side effects.